JPH02131434A - Medicinal composition - Google Patents
Medicinal compositionInfo
- Publication number
- JPH02131434A JPH02131434A JP63285566A JP28556688A JPH02131434A JP H02131434 A JPH02131434 A JP H02131434A JP 63285566 A JP63285566 A JP 63285566A JP 28556688 A JP28556688 A JP 28556688A JP H02131434 A JPH02131434 A JP H02131434A
- Authority
- JP
- Japan
- Prior art keywords
- chitosan
- molecular weight
- drug
- low molecular
- poorly soluble
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 162
- 229940079593 drug Drugs 0.000 claims abstract description 153
- 229920001661 Chitosan Polymers 0.000 claims abstract description 133
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 abstract description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 28
- 238000004090 dissolution Methods 0.000 abstract description 27
- 238000010521 absorption reaction Methods 0.000 abstract description 21
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000002245 particle Substances 0.000 abstract description 9
- 238000005469 granulation Methods 0.000 abstract description 7
- 230000003179 granulation Effects 0.000 abstract description 7
- 239000007921 spray Substances 0.000 abstract description 7
- 239000007962 solid dispersion Substances 0.000 description 37
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 30
- 229960002390 flurbiprofen Drugs 0.000 description 28
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 28
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 21
- 238000002156 mixing Methods 0.000 description 19
- 238000010828 elution Methods 0.000 description 15
- 229960000905 indomethacin Drugs 0.000 description 15
- 238000010298 pulverizing process Methods 0.000 description 14
- -1 nitrite ions Chemical class 0.000 description 13
- 239000006069 physical mixture Substances 0.000 description 13
- 229920002101 Chitin Polymers 0.000 description 12
- 230000002378 acidificating effect Effects 0.000 description 12
- 229930003427 Vitamin E Natural products 0.000 description 11
- 229930003448 Vitamin K Natural products 0.000 description 11
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 11
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 11
- 235000019165 vitamin E Nutrition 0.000 description 11
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- 239000011709 vitamin E Substances 0.000 description 11
- 235000019168 vitamin K Nutrition 0.000 description 11
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- 239000000243 solution Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- 239000002253 acid Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 6
- 229960002537 betamethasone Drugs 0.000 description 6
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 6
- 229960005156 digoxin Drugs 0.000 description 6
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 6
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
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- 229960002036 phenytoin Drugs 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000004898 kneading Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229920000742 Cotton Polymers 0.000 description 4
- 241000238557 Decapoda Species 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- 229950007634 kitasamycin Drugs 0.000 description 4
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 description 4
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 238000004513 sizing Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000007974 sodium acetate buffer Substances 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- QHZUABXEBRGBLP-LKWYKXIFSA-N (6aR,9R,10aR)-N-[(2R,4R,9aS,9bR)-4-benzyl-9b-hydroxy-3,5-dioxo-2-propan-2-yl-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide (6aR,9R,10aR)-N-[(2R,4R,9aS,9bR)-9b-hydroxy-3,5-dioxo-2,4-di(propan-2-yl)-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide (6aR,10aR)-N-[(2S,4S,9bS)-9b-hydroxy-4-(2-methylpropyl)-3,5-dioxo-2-propan-2-yl-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)C4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2CC(CN(C)[C@@H]2C2)C(=O)N[C@@]3(C(=O)C4[C@@H](C(N5CCCC5[C@@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(C21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 QHZUABXEBRGBLP-LKWYKXIFSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 2
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 description 2
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- 241000131500 Chionoecetes opilio Species 0.000 description 2
- 108010022172 Chitinases Proteins 0.000 description 2
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- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 2
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 2
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- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 2
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- ZPACYDRSPFRDHO-ROBAGEODSA-N Gefarnate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(=O)OC\C=C(/C)CCC=C(C)C ZPACYDRSPFRDHO-ROBAGEODSA-N 0.000 description 2
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- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
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- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
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- 229960001789 papaverine Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- Pharmacology & Pharmacy (AREA)
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
〔産業上の利用分野〕
本発明は、低分子量キトサンと難溶性薬剤とを含有する
薬剤組成物に関する６
〔従来の技術〕
一般に、難溶性医薬品と称される医薬品は水に対する溶
解性が極めて悪く、従って生体に経口投与した場合の吸
収速度が遅く、絶対的な吸収量も少ない場合が多い。従
って水に溶け易くするために塩酸塩やナトリウム塩とい
った塩の形にしたり，水溶性のプロドラッグにする試み
がなされている。
また製剤的見地から、界面活性剤のような可溶化剤を添
加したり，サイクロデキストリン等で包接化する試みが
なされている。また結晶レベルでは、原末を微粉化した
り、非品質化したりする試みがなされている。
しかし、これらの従来技術は医薬品それぞれで有効な方
法が異なるため、すκでの医薬品に有効な方法とは言い
難く、特に難溶性医薬品の絶対的な吸収量を改善できて
も，必ずしも吸収速度の改善はできないのが現状である
。ところが、難溶性医薬品の中にはその薬理効果の面か
ら速効性を期待される医薬品も多くまれでおり、吸収景
の面からのみではなく、吸収速度の面からも良好な経口
投与製剤が望まれている。
このような状況の中で、雅溶性薬剤の吸収性の改善に種
々の高分子を利用することが検討されている。
高分子量のゼラチンを利用する方法として、特開昭５７
−２６６１５号には、難溶性薬剤と高分子量のゼラチン
等を共粉砕する方法が記載されている。しかし、この方
法は難溶性薬剤の吸収改善のために添加するゼラチン量
が多く、また製造法も共粉砕法に限られているという欠
点がある。
一方、カニやエビの甲殻から得られるキチンやキトサン
を製剤に利用する試みもなされている．ところが、キチ
ンやキトサンの利用は、薬剤の徐放化の目的で検討され
ているのが大部分であり、難溶性薬剤の可溶化に関する
ものはまだ少ない．特公昭６３−２８４１４号には、キ
チンおよび／またはキトサンと，抗生物質および抗てん
かん剤から選ばれるいずれか１種の難溶性薬剤とを、薬
剤の大部分が非結晶化する程度に混合共粉砕し，薬剤の
吸収速度および吸収量を改善する方法が記載されている
。しかし、この方法は、低分子量のキトサンを開示して
おらず、また混合共粉砕には多大な時間と動力を要する
とともに、製剤工程が複雑化するという問題点がある。
また，キタサマイシンと各種高分子化合物とをロール混
合することにより、キタサマイシンの溶解速度を向上さ
せる方法が報告されており〔表面，２６（５）３３６（
１９８８）） 、この中でキトサンは酢酸塩溶液として
用いるが、ポリビニルピロリドンの効果に比較すると劣
ったものとなっている。
〔発明が解決しようとする課題〕
本発明の目的は、上記のような問題点を解決するため、
種々の難溶性薬剤の水に対する溶解度と溶出速度が改善
された薬剤組成物を提供することである．さらに、湿式
法、乾式法，共粉砕法、噴霧造粒法等の製剤法が利用で
きる難溶性薬剤を含有する薬剤組成物を提供することで
ある。
〔課題を解決するための手段〕
本発明者らは、難溶性医薬品の溶解性改善のために種々
の高分子の添加効果を検討してきた。その結果、低分子
量キトサンと難溶性薬剤とを混合することにより、難溶
性薬剤の溶解度と溶出速度が改善されることを発見し本
発明を完成した。
すなわち、本発明は、低分子量キトサンと難溶性薬剤と
を含有する薬剤組成物である。
本発明で使用する低分子量キトサンは，天然のキチンか
ら得られるキトサンの低分子化物であり、重量平均分子
量が５００〜５０ Ｘ １０３．好ましくは８００〜１
０ Ｘ １０’で、酸性はもちろん， 中性ないしアル
カリ性の水に溶解するキトサンである。重量平均分子量
が５００未満の場合およびｓｏ ｘ ｉｏ’を超える場
合は，難溶性薬剤の溶解度と溶出速度の改善効果が小さ
くなる。重量平均分子量は、ゲルパーミエーションク口
マトグラフィーにより分子量既知のポリエチレングリコ
ールを標準として決定できる．低分子量キトサンの原料
となるキトサンは，カニやエビの甲殻などからキチンを
とりだし、アルカリで脱アセチル化することにより得ら
れる高分子物質である。この場合のキトサンの脱アセチ
ル化の程度は特に限定されるものではなく、酸性水溶液
に可溶な範囲であればよい．このようなキトサンから低
分子量キトサンを得るには，キトサンに酵素を作用させ
る酵素的方法、あるいはキトサンに過酸化水素、亜硝酸
イオン、アルカリ、酸などを加えてグルコシド結合を切
断する化学的方法により、低分子量キトサンを得ること
ができる。
化学的方法により低分子量キトサンを得るには，キトサ
ンをアルカリ液中に懇濁させ，適量の過酸化水素を添加
して一定温度下に一定時間反応させ低分子化し、その後
説塩，分子量分画等の精製を行い，水分除去後乾燥して
粉末化すればよい。キトサンを切断し低分子化する条件
は．ＰＨ６〜１２、過酸化水素濃度０．００５〜１０重
量％、液温２０〜９０℃、反応時間３０〜５００分程度
が好ましい．また酵素的方法によれば，キトサンとキチ
ナーゼまたはキトサナーゼを接触させて低分子化する。
その後上述の方法で粉末化すればよい．本発明において
使用できる難溶性薬剤は難溶性医薬品が例示され、その
生体内への吸収速度あるいは吸収量（パイオアベイラビ
リティ）が充分とは言えない医薬品であれば特に限定さ
れない。このような医薬品としては、例えば以下のもの
があげられる。
イ）催眠・鎮静剤：
例えば、ニトラゼパム、トリアゾラム、フェノバルビタ
ール、アミバルビタール等
α》抗てんかん剤：
例えば、フェニトイン、メタルビタール，プリミドン、
クロナゼバム、カルバマゼピン、バルプロ酸等
ハ）解熱鎮痛消炎剤：
フルルビプロフェン、メフェナム酸，ケトプロフェン、
イブプロフェン、インドメタシン，ジクロフェナク酸、
フエナセチン、オキシフェンブタゾン，フェニルブタゾ
ン，スルビリン，ペンタゾシン、ピロキシカム等
二）鎮うん剤：
塩酸メクリジン，ジメンヒドリナート等幻精神神経用剤
：
ハロペリドール、メプロバメート、クロルジアゼポキシ
ド、ジアゼパム，オキサゼバム、スルピリド等
へ）鎮けい剤：
パバベリン、アトロピン、エトミドリン等ト）強心剤：
ジゴキシン、ジギトキシン、メチルジゴキシン、ユビデ
カレノン等
チ）不整脈用剤：
ビンドロール、アジマリン、ジソビラミド等り）利尿剤
：
ヒドロクロ口チアジド，スピロノラクトン、トリアムテ
レン、フロセミド、ブメタニド等ヌ）杭高血圧剤：
レセルピン、メシル酸ジヒドロエルゴトキシン，塩酸プ
ラゾシン、メトプロロール、プロプラノロール、アテノ
ロール等
ル）冠血管拡張剤：
ニトログリセリン、硝酸イソソルビド、ジルチアゼム，
ニフエジピン、ジピリダモーノレ等ヲ）鎮咳剤：
ノスカピン、サルブタモール、プロ力テロール，ツロプ
テロール、トラニラスト，ケトチフェン等
ワ）脳循環改善剤：
二カルジピン、ピンポセチン等
力）抗生物質：
エリスロマイシン、ジョサマイシン、クロフムフェニコ
ール，テトラサイクリン，リファンピシン，グリセオフ
ルビン等
ヨ）抗ヒスタミン剤：
ジフェンヒドラミン，プロメタジン、メキタジン等
タ）ステロイド剤：
トリアムシノロン、デキサメタゾン、ベタメタゾン，プ
レドニゾロン、ダナゾール、メチルテストステロン、酢
酸クロルマジノン等レ）ビタミン剤：
ビタミンＥ、ビタミンＫ、アルファ力ルシドール、フィ
トナジオン，ニコチン酸ｄｉ一α一トコフェロール、メ
ナテトレノン等
ン）その他：
ジクマロール、シンナリジン、クロフィブラート、ゲフ
ァルナート、シメチジン，プロベネシド、メルカプトプ
リン、メトトレキサート，ウルソデスオキシコール酸，
メシル酸ジヒドロエルゴタミン等
上記の難溶性医薬品は原末の溶解性の面から、湿式また
は乾式の粉砕機で粉砕して得られる平均粒径１００μＩ
以下，好ましくは５０μｍ以下であることが望ましい。
本発明の薬剤組成物は，前記の低分子量キトサンが上記
の難溶性薬剤に対して均一に分散するように混合して製
造するのが望ましい。この場合、低分子量キトサンは，
混合する難溶性薬剤の種類により適宜量使用すればよい
．一般的には、難溶性薬剤１重址部に対して低分子量キ
トサンを０．２ないし１０重量部配合すれば、難溶性薬
剤の溶解度と溶出速度を改善することができる。
本発明の薬剤組成物は、種々の方法により製剤化してヒ
トに投薬することができる。すなわち、本発明の薬剤組
成物は、そのまま顆粒剤として用いることができるが，
錠剤，カプセル剤、軟膏，貼布剤、座剤、シロップ剤、
トローチ剤などとして用いることもできる。これらの製
剤中には必要に応じて製剤上知られる賦形剤、崩壊剤、
滑沢剤等の種々の添加剤を配合することができる。
本発明の薬剤組成物は、次のような方法で製剤化するこ
とができる。錠剤は、低分子量キトサンと難溶性薬剤と
を水，酸溶液あるいは適当な溶媒を用いて練合し、乾燥
、整粒、打錠を行う練合法、また低分子量キトサンと難
溶性薬剤とを練合し、乾燥、整粒後、種々の添加剤を混
合し、打錠を行う半直打法といった湿式法．低分子量キ
トサンの量を調整することにより乾式法あるいは共粉砕
法等により製造することができる．これらの中では湿式
法により固体分散体とするのが好ましい。顆粒剤および
カプセル剤においても錠剤の場合と同様に湿式法により
製剤化するのが好ましレ１が、場合によっては乾式法や
共粉砕法あるいは噴霧造粒法等も採用することができる
。また、錠剤および顆粒剤などの剤形においては，マス
キング等の目的でコーティングを施すこともできる。
以上のようにして製造した製剤は、従来のものに比べて
難溶性薬剤の溶解度と溶出速度が改善されているため、
パイオアベイラビリテイの良好な医薬品となる。
〔発明の効果〕
本発明によれば、難溶性薬剤を低分子量キトサンと配合
するようにしたので、難溶性薬剤の溶解度と溶出速度が
改善された薬剤組成物を得ることができる．さらに、こ
の薬剤組成物から湿式法、乾式法、共粉砕法、噴霧造粒
法等の製剤法により種々の形態の製剤を得ることができ
る。
〔実施例〕
次に、本発明の実施例について説明する。
参考例１
紅ずわいがにから常法によりキトサンを得た（以下，Ｃ
−０と略記する）．このキトサンを水に｝萄濁させ、Ｐ
ＨＩＩ，０、温度を７０℃に保ち，攪拌しながら過酸化
水素水を過酸化水素として２．１〜４０．０ｇ／ｉｌｌ
添加して、１１０〜３００分間反応させて低分子化した
．低分子化した後脱塩精製し、次いで凍結乾燥し、第１
表に示す低分子量キトサンＣ−１、Ｃ−２、Ｃ−３およ
びＣ−４を得た．また、同様にキトサン（Ｃ−Ｏ）をｐ
｝！８．０、温度を７０℃に保ち、攪拌しながら過酸化
水素水を過酸化水素として４ ０ｇ／Ω添加して低分子
化した．低分子化後濾過により固形分を除き，次いでｔ
］Ｆ膜を用いて分子量分画を行い、凍結乾燥して低分子
量キトサンＣ−５を得た。
このようにして得たキトサンの物性を第１表に示す。第
１表中の蒸発残分は、１０５℃で乾燥させた時の残渣で
あり、灰分は６００℃で燃焼した時の残渣である。キト
サンの分子量は，キトサンを同量の酢酸と適当量の水を
用いて溶解し、この溶液２．０ｍＱを０．２Ｍ酢酸−０
．１Ｍ酢酸ナトリウム緩衝液で５０ｍｊ２とし、これを
東ソー（株）のＴＳＫ Ｇｅｌ． ３０００ ＰＷＸＬ
に掛け０．２Ｍ酢酸−０．１Ｍ酢酸ナトリウム溶出液を
使用して、ゲルパーミエーションク口マトグラフィーで
測定した。なお、分子量既知のポリエチレングリコール
を用いて較正曲線を求め、キトサンの重量平均分子量を
求めた。
第１表
実施例１
参考例１で得たＣ−０からＣ−５のキトサンとフルルビ
プロフェン（以下、ＦＰと略記する場合がある）を重量
比１：１の割合で秤量し、キトサンの２倍量の水を添加
して１時間混練した。室温減圧下４８時間乾燥し、１０
０メッシュ以下の粒子を固体分散体とした。この固体分
散体について、３７℃の水中におけるＦＰの溶出速度を
下記の方法で測定した。
３７℃に保った溶出試験器（富山産業（株）製溶出試験
器）に水５００ｍＱを入れ、上記の固体分散体をＦＰと
して４０ｍｇ相当量加え、９１ｒｐｍで攪拌した，一定
時間毎に綿栓付きピペットで試料溶液を３＋ａＱを採取
し、 ０．４５μｍメンプランフィルターでろ過し、ろ
液のＦＰ濃度をクロロホルムで抽出して定量した。
結果を第１図に示す。
実施例２
ビタミンＥおよびビタミンＫと低分子量キトサンＣ−５
の組成物の溶解度を、下記の方法で測定した。
一定過剰量のビタミンＥまたはビタミンＫを５ｍｇ精秤
して試験管に取り、種々の濃度の参考例１で得たＣ−５
のキトサン水溶液を加えて密栓し、２５℃で１０日間振
盪した。溶解平衡に達した各飽和溶液を綿栓付きピペッ
トでろ取し、０．４５μｍメンプランフィルターでろ過
し，クロロホルムで抽出してＵｖ法によりビタミンＥま
たはビタミンＫの濃度を定景した。
ビタミンＥの結果を第２図，ビタミンＫの結果を第３図
に示す。
実施例３
第２表に示す薬剤と低分子量キトサンＣ−５の組成物に
ついて，溶解度を測定した。測定方法は実施例２と同様
である。結果をまとめて第４図に示す。
第４図から分るように，各薬剤の溶解度は低分子量キト
サンの濃度上昇とともに上昇した．特に酸性薬剤の場合
に著しい上昇がａｍされた．これは塩基性多糖である低
分子量キトサンと酸性薬剤との対イオン形成等の相互作
用が関与しているものと考えられるが、薬剤の解離をあ
まり考慮しなくても良いステロイド剤であるジゴキシン
およびフェニトインの場合にも溶解度が上昇した．また
、ベタメサゾンおよびトリアムシノロンの場合には薬剤
の溶解度の上昇部分、プラト一部分および下降曲線部分
を伴うＢＳ型相図を与えた．これらの結果は、低分子量
キトサンが各薬剤と単に対イオンを形成するだけでなく
、何らかの相互作用をすることにより薬剤の溶解度を上
昇させているものと推定される。
実施例４
トリアムシノロン，ベタメサゾン、プレドニゾロン，フ
ルルビプロフエン、インドメタシン、ジゴキシンおよび
フェニトインの各薬剤の固体分散体と薬剤単独物につい
て溶出速度を測定した。
測定方法は、参考例１で得た低分子量キトサンＣ−５を
用いて、実施例１と同様（但し，薬剤は１０〜３０ｍｇ
相当量加え、溶出液６０ｍｍを５７ｒｐｍで撹拌した）
にして行った．結果をまとめて第５図に示す。なお、フ
ルルビプロフエンの結果については、再掲載する．
さらに、溶出速度から算出した平均溶出時間を第３表に
示す。
第３表
いずれの薬剤においても、固体分散体からの薬剤の溶出
速度は薬剤単独の場合に比べて著しく速くなった。酸性
薬剤の場合には、実施例３の結果から明らかなように、
薬剤の溶解度上昇に伴う溶出速度の増大が考えられるが
、溶解度の上昇があまり認められなかった薬剤において
も著しい溶出速度の増大が観察された．
実施例５
フルルビプロフェンと参考例ｌで得た低分子量キトサン
Ｃ−５の粉末を重量比１：３の割合で単純に混合しただ
けの物理的混合物と、フルルビプロフェンとＣ−５の配
合割合を重量比１：３に代えた以外は実施例１と同様に
して得た固体分散体について、粉末Ｘ線回折を行った．
粉末Ｘ線は理学電気■製Ｇｅｉｇｅｒ Ｆｌｅｘ ２１
０２ Ｘ線回折装置を使用し、Ｃｕ−Ｋａ線、 Ｎｉフ
ィルターを用い、３０ｋＶ、２０ｍＡ，時定数２ ｓｅ
ｃ、走査速度１℃／ｗｉｎで測定した．インドメタシン
、ジゴキシン，トリアムシノロンについても同様にして
粉末Ｘ線回折を行った．結果を第６図に示す。
粉末Ｘ線回折パターンは薬剤の結晶系および充填状態に
関する情報を与える．第６図から分るように、低分子量
キトサン単独は非品質性物質であるため、物理的混合物
の場合には薬剤特有の特性ピークがａｍされるだけであ
る。酸性薬剤のフルルビプロフェンの場合には、物理的
混合物で観察された薬剤の特性ピークが固体分散体では
ｉ察されず，フルルビプロフェンが低分子量キトサン中
に非晶質化して分散していることを示した。しかしなが
ら他の３つの薬剤の固体分散体は物理的混合物と全く同
じ回折パターンを示し、低分子量キトサン添加による薬
剤の結晶性の低下は認められなかった。
実施例６
融点が低分子量キトサンより低いフルルビプロフェンと
インドメタシンについて示差熱量を測定した。測定に使
用した試料は、実施例５で得た物理的混合物、固体分散
体，低分子量キトサン単独物、薬剤単独物である。示差
熱量は、理学電気■１！Ｔｈｅｒｍｏｆｌｅｘ ＴＧ−
８１１０を使用し、試料は薬剤単独として５ＩＩＩｇを
昇温速度１０℃／ｗｉｎで、α−アルミナを標準物質に
用いて測定した。
結果を第７図に示す．
示差熱量は，薬剤の融解に基づく吸熱ピークをＩＮ察す
ることにより、固体中の薬剤の状態を知ることができる
．第７図から分るように、フルルビプロフェンの固体分
散体の場合には，薬剤の融解に基づくピークが消失し、
フルルビプロフェンが低分子量キトサンとの固体分散体
中に結晶性を失って分散していることを示した。しかし
ながら、インドメタシンの場合には、固体分散体におい
ても薬剤の融解ピークがみられ，インドメタシンは結晶
性を保ったまま固体分散体中に分散していることを示し
た。これらの結果は実施例５の結果と一致しており，フ
ルルビプロフェンは低分子量キトサンと固体状態におい
て何らかの相互作用をして，低分子量キトサンとの固体
分散体中に非品質化して存在するが、他の薬剤は低分子
量キトサンとほとんど相互作用せずに、結晶性を有した
まま固体分散体中に存在することが推定される．実施例
７
フルルビプロフェン、インドメタシン、およびトリアム
シノロンについて薬剤粒子表面のぬれを測定した．測定
に使用した試料は、実施例５で得た固体分散体と薬剤単
独物である。ぬれは． ＩＲ打錠機により直径２ｃｍの
錠剤を成形し、その表面に５０μΩの水を落として、接
触角を測定することにより求めた．
結果を第４表に示す．
第４表
第４表から分るように、薬剤単独の接触角に比べて、低
分子量キトサンとの固体分散体のそれは低下した．これ
らの結果から低分子量キトサンは薬物粒子表面水に対す
るぬれを改善することにより溶出速度を上昇させるもの
と推定される。
実施例８
フルルビブロフェンと、参考例１で得た低分子量キトサ
ンＣ−２、Ｃ−４またはＣ−５との混線体（重量比で１
：１または１：５）からＨ−１５ （カカオ油脂）を基
剤として坐剤をつくり、この坐剤からのフルルビプロフ
ェンの放出率を測定した。
結果を第８図に示す．[Industrial Application Field] The present invention relates to a pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug.6 [Prior Art] In general, pharmaceuticals called poorly soluble pharmaceuticals have extremely poor solubility in water. Therefore, when administered orally to a living body, the absorption rate is slow and the absolute amount absorbed is often small. Therefore, attempts have been made to make them more easily soluble in water by converting them into salt forms such as hydrochloride or sodium salt, or by making them into water-soluble prodrugs. Also, from a pharmaceutical standpoint, attempts have been made to add solubilizers such as surfactants or to clathrate them with cyclodextrins. Furthermore, at the crystal level, attempts have been made to pulverize or degrade the bulk powder. However, these conventional techniques have different effective methods for each drug, so it is difficult to say that they are effective methods for drugs with low soluble properties.Even if the absolute absorption amount of poorly soluble drugs can be improved, it does not necessarily affect the absorption rate. The current situation is that it is not possible to improve. However, there are many poorly soluble drugs that are expected to be fast-acting due to their pharmacological effects, and oral preparations that are good not only in terms of absorption profile but also in terms of absorption speed are desirable. It is rare. Under these circumstances, the use of various polymers to improve the absorption of soluble drugs is being considered. As a method of using high molecular weight gelatin, JP-A-57
No. 26615 describes a method of co-pulverizing a poorly soluble drug and high molecular weight gelatin. However, this method has disadvantages in that a large amount of gelatin is added to improve the absorption of poorly soluble drugs, and the production method is also limited to co-pulverization. On the other hand, attempts have also been made to use chitin and chitosan obtained from crab and shrimp shells in pharmaceutical preparations. However, most of the uses of chitin and chitosan have been investigated for the purpose of sustained release of drugs, and there are still few studies on the use of chitin and chitosan for solubilizing poorly soluble drugs. Japanese Patent Publication No. 63-28414 discloses that chitin and/or chitosan and one poorly soluble drug selected from antibiotics and antiepileptic drugs are mixed and co-pulverized to such an extent that most of the drug becomes amorphous. and methods to improve the rate and amount of drug absorption are described. However, this method does not disclose low-molecular-weight chitosan, and there are problems in that mixing and co-pulverization requires a great deal of time and power, and the formulation process becomes complicated. In addition, a method for improving the dissolution rate of kitasamycin by roll mixing kitasamycin and various polymer compounds has been reported [Surface, 26(5) 336(
(1988)), in which chitosan is used as an acetate solution, but its effectiveness is inferior to that of polyvinylpyrrolidone. [Problems to be Solved by the Invention] The purpose of the present invention is to solve the above-mentioned problems.
The object of the present invention is to provide drug compositions in which the water solubility and dissolution rate of various poorly soluble drugs are improved. Another object of the present invention is to provide a pharmaceutical composition containing a poorly soluble drug that can be applied to formulation methods such as a wet method, a dry method, a co-pulverization method, and a spray granulation method. [Means for Solving the Problems] The present inventors have investigated the effects of adding various polymers to improve the solubility of poorly soluble pharmaceuticals. As a result, the present invention was completed by discovering that the solubility and elution rate of a poorly soluble drug can be improved by mixing low molecular weight chitosan with a poorly soluble drug. That is, the present invention is a pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug. The low molecular weight chitosan used in the present invention is a low molecular weight chitosan obtained from natural chitin, and has a weight average molecular weight of 500 to 50 x 103. Preferably 800-1
0 x 10', chitosan is soluble in acidic as well as neutral to alkaline water. When the weight average molecular weight is less than 500 and when it exceeds so x io', the effect of improving the solubility and elution rate of poorly soluble drugs becomes small. The weight average molecular weight can be determined by gel permeation chromatography using polyethylene glycol of known molecular weight as a standard. Chitosan, the raw material for low-molecular-weight chitosan, is a polymeric substance obtained by extracting chitin from crab and shrimp shells and deacetylating it with alkali. The degree of deacetylation of chitosan in this case is not particularly limited, and may be within a range that is soluble in an acidic aqueous solution. In order to obtain low molecular weight chitosan from such chitosan, there is an enzymatic method in which enzymes are applied to chitosan, or a chemical method in which hydrogen peroxide, nitrite ions, alkali, acid, etc. are added to chitosan to cleave glucoside bonds. , low molecular weight chitosan can be obtained. To obtain low-molecular-weight chitosan by a chemical method, chitosan is suspended in an alkaline solution, an appropriate amount of hydrogen peroxide is added, the reaction is carried out at a certain temperature for a certain period of time, and the molecular weight is reduced. After removing moisture, it may be dried and powdered. What are the conditions for cutting chitosan and making it into a low molecular weight product? Preferably, the pH is 6 to 12, the hydrogen peroxide concentration is 0.005 to 10% by weight, the liquid temperature is 20 to 90°C, and the reaction time is about 30 to 500 minutes. According to the enzymatic method, chitosan is brought into contact with chitinase or chitosanase to reduce the molecular weight. After that, it can be powdered using the method described above. The poorly soluble drug that can be used in the present invention is exemplified by a poorly soluble drug, and is not particularly limited as long as the drug has insufficient absorption rate or absorption amount (bioavailability) into the body. Examples of such medicines include the following: b) Hypnotic/sedative agents: For example, nitrazepam, triazolam, phenobarbital, amibarbital, etc.α》 Antiepileptic agents: For example, phenytoin, metalbital, primidone,
Clonazebam, carbamazepine, valproic acid, etc. c) Antipyretic, analgesic and anti-inflammatory agents: flurbiprofen, mefenamic acid, ketoprofen,
Ibuprofen, indomethacin, diclofenacic acid,
phenacetin, oxyphenbutazone, phenylbutazone, sulvirine, pentazocine, piroxicam, etc. 2) Antidepressants: meclizine hydrochloride, dimenhydrinate, etc. Phantom neuropsychiatric agents: haloperidol, meprobamate, chlordiazepoxide, diazepam, oxazebam, sulpiride, etc.) Antispasmodics: pababerine, atropine, etomidrine, etc.) Inotropes: digoxin, digitoxin, methyldigoxin, ubidecarenone, etc.) Arrhythmic agents: vindolol, ajmaline, disobiramide, etc.) Diuretics: hydrocrothiazide, spironolactone, triamterene, furosemide, Bumetanide, etc. Hypertensive agents: Reserpine, dihydroergotoxin mesylate, prazosin hydrochloride, metoprolol, propranolol, atenolol, etc.) Coronary vasodilators: Nitroglycerin, isosorbide nitrate, diltiazem,
Nifedipine, dipyridamone, etc.) Antitussives: noscapine, salbutamol, proterol, tulopterol, tranilast, ketotifen, etc.) Cerebral circulation improving agents: dicardipine, pinpocetine, etc.) Antibiotics: erythromycin, josamycin, clohumuphenicol, tetracycline, Rifampicin, griseofulvin, etc. Antihistamines: diphenhydramine, promethazine, mequitazine, etc. Steroids: triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate, etc. Vitamins: vitamin E, vitamin K, alpha-lucidol, phytonadione, di-alpha-tocopherol nicotinate, menatetrenone, etc.) Others: dicoumarol, cinnarizine, clofibrate, gefarnate, cimetidine, probenecid, mercaptopurine, methotrexate, ursodesoxycholic acid,
Due to the solubility of the bulk powder, the above-mentioned poorly soluble drugs such as dihydroergotamine mesylate can be ground with a wet or dry grinder with an average particle size of 100μI.
The thickness is preferably 50 μm or less. The drug composition of the present invention is preferably manufactured by mixing the low molecular weight chitosan with the poorly soluble drug so that it is uniformly dispersed. In this case, low molecular weight chitosan is
The appropriate amount should be used depending on the type of poorly soluble drug to be mixed. Generally, the solubility and dissolution rate of a poorly soluble drug can be improved by blending 0.2 to 10 parts by weight of low molecular weight chitosan to one part of the poorly soluble drug. The pharmaceutical composition of the present invention can be formulated and administered to humans by various methods. That is, the pharmaceutical composition of the present invention can be used as a granule as it is, but
Tablets, capsules, ointments, patches, suppositories, syrups,
It can also be used as a troche. These preparations contain excipients, disintegrants, and
Various additives such as lubricants can be blended. The pharmaceutical composition of the present invention can be formulated by the following method. Tablets can be made by kneading low molecular weight chitosan and a poorly soluble drug using water, an acid solution or an appropriate solvent, drying, sizing and tableting, or by kneading low molecular weight chitosan and a poorly soluble drug. A wet method such as a semi-direct compression method in which various additives are mixed after combining, drying, and sizing, and the tablets are compressed. By adjusting the amount of low molecular weight chitosan, it can be produced by dry method or co-pulverization method. Among these, it is preferable to form a solid dispersion by a wet method. Granules and capsules are preferably formulated by a wet method as in the case of tablets, but dry methods, co-pulverization methods, spray granulation methods, etc. may also be employed depending on the case. In addition, dosage forms such as tablets and granules may be coated for purposes such as masking. The preparations produced as described above have improved solubility and dissolution rate of poorly soluble drugs compared to conventional preparations.
It is a drug with good availability. [Effects of the Invention] According to the present invention, since a poorly soluble drug is blended with low molecular weight chitosan, it is possible to obtain a drug composition in which the solubility and dissolution rate of the poorly soluble drug are improved. Furthermore, preparations in various forms can be obtained from this pharmaceutical composition by formulation methods such as a wet method, a dry method, a co-pulverization method, and a spray granulation method. [Example] Next, an example of the present invention will be described. Reference Example 1 Chitosan was obtained from red snow crab by a conventional method (hereinafter referred to as C
(abbreviated as -0). This chitosan is suspended in water, and P
HII, 0, keep the temperature at 70°C and add 2.1 to 40.0 g/ill of hydrogen peroxide as hydrogen peroxide while stirring.
was added and reacted for 110 to 300 minutes to reduce the molecular weight. After reducing the molecular weight, it is desalted and purified, then freeze-dried, and the first
Low molecular weight chitosans C-1, C-2, C-3 and C-4 shown in the table were obtained. Similarly, chitosan (C-O) was added to p
}! 8.0, the temperature was maintained at 70°C, and 40 g/Ω of hydrogen peroxide was added while stirring to reduce the molecular weight. After reducing the molecular weight, the solid content is removed by filtration, and then t
]F membrane to perform molecular weight fractionation and freeze drying to obtain low molecular weight chitosan C-5. The physical properties of the chitosan thus obtained are shown in Table 1. The evaporation residue in Table 1 is the residue when dried at 105°C, and the ash is the residue when burned at 600°C. The molecular weight of chitosan can be determined by dissolving chitosan using the same amount of acetic acid and an appropriate amount of water, and adding 2.0 mQ of this solution to 0.2 M acetic acid-0.
．． The concentration was adjusted to 50 mj2 with 1M sodium acetate buffer, and this was added to TSK Gel. 3000 PWXL
It was measured by gel permeation chromatography using a 0.2M acetic acid-0.1M sodium acetate eluate. A calibration curve was determined using polyethylene glycol of known molecular weight, and the weight average molecular weight of chitosan was determined. Table 1 Example 1 C-0 to C-5 chitosan obtained in Reference Example 1 and flurbiprofen (hereinafter sometimes abbreviated as FP) were weighed at a weight ratio of 1:1, and chitosan Two times the amount of water was added and kneaded for 1 hour. Dry at room temperature under reduced pressure for 48 hours,
Particles with a size of 0 mesh or less were used as a solid dispersion. Regarding this solid dispersion, the elution rate of FP in water at 37°C was measured by the following method. 500 mQ of water was placed in a dissolution tester (dissolution tester manufactured by Toyama Sangyo Co., Ltd.) maintained at 37°C, and an amount equivalent to 40mg of the above solid dispersion as FP was added, followed by stirring at 91 rpm, with a cotton plug attached at regular intervals. A sample solution of 3+aQ was collected with a pipette, filtered through a 0.45 μm membrane filter, and the FP concentration of the filtrate was extracted and quantified with chloroform. The results are shown in Figure 1. Example 2 Vitamin E and vitamin K and low molecular weight chitosan C-5
The solubility of the composition was measured by the following method. Precisely weigh 5 mg of a certain excess amount of vitamin E or vitamin K, put it in a test tube, and prepare the C-5 obtained in Reference Example 1 at various concentrations.
An aqueous chitosan solution was added thereto, the tube was tightly stoppered, and the tube was shaken at 25° C. for 10 days. Each saturated solution that had reached solubility equilibrium was collected by filtration using a pipette with a cotton stopper, filtered through a 0.45 μm membrane filter, extracted with chloroform, and the concentration of vitamin E or vitamin K was determined using the UV method. The results for vitamin E are shown in Figure 2, and the results for vitamin K are shown in Figure 3. Example 3 The solubility of the compositions of the drugs shown in Table 2 and low molecular weight chitosan C-5 was measured. The measurement method is the same as in Example 2. The results are summarized in Figure 4. As can be seen from Figure 4, the solubility of each drug increased as the concentration of low molecular weight chitosan increased. A marked increase was observed especially in the case of acidic drugs. This is thought to be related to the interaction between low molecular weight chitosan, which is a basic polysaccharide, and the acidic drug, such as the formation of counter ions. The solubility of phenytoin also increased. In addition, in the case of betamethasone and triamcinolone, a BS-type phase diagram with an increasing part, a plateau part, and a descending curve part of drug solubility was given. These results suggest that low molecular weight chitosan not only forms a counter ion with each drug, but also interacts with it in some way to increase the solubility of the drug. Example 4 The dissolution rates were measured for solid dispersions and individual drugs of triamcinolone, betamethasone, prednisolone, flurbiprofen, indomethacin, digoxin, and phenytoin. The measurement method was the same as in Example 1, using the low molecular weight chitosan C-5 obtained in Reference Example 1 (however, the drug was 10 to 30 mg).
A corresponding amount was added, and 60 mm of the eluate was stirred at 57 rpm)
I went there. The results are summarized in Figure 5. The results for flurbiprofen will be republished. Furthermore, the average elution time calculated from the elution rate is shown in Table 3. For all drugs in Table 3, the elution rate of the drug from the solid dispersion was significantly faster than that of the drug alone. In the case of acidic drugs, as is clear from the results of Example 3,
It is thought that the dissolution rate increases as the solubility of the drug increases, but a significant increase in the dissolution rate was observed even for drugs that did not show a significant increase in solubility. Example 5 A physical mixture in which flurbiprofen and the low molecular weight chitosan C-5 powder obtained in Reference Example 1 were simply mixed at a weight ratio of 1:3, and a physical mixture of flurbiprofen and C-5 Powder X-ray diffraction was performed on a solid dispersion obtained in the same manner as in Example 1 except that the weight ratio of .
The powder X-ray is Geiger Flex 21 manufactured by Rigaku Denki.
02 Using an X-ray diffraction device, using Cu-Ka rays and Ni filter, 30 kV, 20 mA, time constant 2 se
c. Measured at a scanning speed of 1°C/win. Powder X-ray diffraction was performed in the same manner for indomethacin, digoxin, and triamcinolone. The results are shown in Figure 6. Powder X-ray diffraction patterns provide information about the crystal system and packing state of the drug. As can be seen from FIG. 6, since low molecular weight chitosan alone is a non-quality substance, in the case of a physical mixture, only characteristic peaks unique to the drug are observed. In the case of the acidic drug flurbiprofen, the characteristic peak of the drug observed in the physical mixture was not observed in the solid dispersion, indicating that flurbiprofen was amorphous and dispersed in the low molecular weight chitosan. It was shown that However, the solid dispersions of the other three drugs showed exactly the same diffraction patterns as the physical mixtures, and no decrease in the crystallinity of the drugs was observed due to the addition of low molecular weight chitosan. Example 6 Differential calorific value was measured for flurbiprofen and indomethacin, both of which have melting points lower than that of low molecular weight chitosan. The samples used in the measurements were the physical mixture, solid dispersion, low molecular weight chitosan alone, and drug alone obtained in Example 5. Differential calorific value is Rigaku Denki ■1! Thermoflex TG-
8110, the sample was measured using 5IIIg as a drug alone at a heating rate of 10° C./win, and using α-alumina as a standard substance. The results are shown in Figure 7. Differential calorific value can determine the state of a drug in a solid by observing the endothermic peak due to melting of the drug. As can be seen from Figure 7, in the case of the solid dispersion of flurbiprofen, the peak due to the melting of the drug disappears,
It was shown that flurbiprofen lost its crystallinity and was dispersed in a solid dispersion with low molecular weight chitosan. However, in the case of indomethacin, a melting peak of the drug was observed even in the solid dispersion, indicating that indomethacin was dispersed in the solid dispersion while maintaining its crystallinity. These results are consistent with the results of Example 5, indicating that flurbiprofen has some kind of interaction with low molecular weight chitosan in the solid state and exists in a non-quality form in the solid dispersion with low molecular weight chitosan. However, it is presumed that other drugs hardly interact with low molecular weight chitosan and remain crystalline in the solid dispersion. Example 7 Wetting of drug particle surfaces was measured for flurbiprofen, indomethacin, and triamcinolone. The samples used in the measurement were the solid dispersion obtained in Example 5 and the drug alone. The wetness. The contact angle was determined by forming a tablet with a diameter of 2 cm using an IR tablet press, dropping 50 μΩ of water onto the surface of the tablet, and measuring the contact angle. The results are shown in Table 4. Table 4 As can be seen from Table 4, the contact angle of the solid dispersion with low molecular weight chitosan was lower than that of the drug alone. From these results, it is presumed that low molecular weight chitosan increases the dissolution rate by improving the wettability of the drug particle surface to water. Example 8 Mixer of flurbibrofen and low molecular weight chitosan C-2, C-4 or C-5 obtained in Reference Example 1 (weight ratio: 1
:1 or 1:5) to make suppositories using H-15 (cocoa oil and fat) as a base, and the release rate of flurbiprofen from these suppositories was measured. The results are shown in Figure 8.
第１図は実施例１の結果を示すグラフ，第２図および第
３図は実施例２の結果を示すグラフ、第４図（Ａ）〜（
Ｌ）は実施例３の結果を示すグラフ、第５図（Ａ）〜（
Ｇ）は実施例４の結果を示すグラフ，第６図（Ａ）〜（
Ｄ）は実施例５の結果を示すグラフ、第７図（Ａ）．
（Ｂ）は実施例６の結果を示すグラフ、第８図は実施例
８の結果を示すグラフである．第１図
Ｓ工吟間（分）
代理人 弁理士 柳 原 成
第２図
第４図
（Ａ）
ＣＢ）
Ｃ−５ ヘトプンの５農度（Ｉｔ’ん》第３図
Ｃ−５ ベトプ冫０５泉Ｊ隻（．１１／．）Ｃ−５
ベトプンの須／ｔ（ｉｔ’／ＪＣ−５ そトブンリチ
ｌａ＜ｖ量０ｌ０）第４図
第４図
（Ｅ）
（Ｆ）
Ｃ−５ モトプノリシ賓，１（−１ｔ°／．）Ｃ−５
子｝プ〉の堺し％（重．ｔ’／．）Ｃ−５Ｎ｝ブ＞ｎ
Ｊ／ｔ （菫ｔ’／．）Ｃ−５ 大トブン弓漢／ｌ（
菫１０Ｉ０）（Ｇ）
（Ｈ）
Ｃ−５ へドブンつゾＬ度（里子０１０）Ｃ−５
’ｒ’ｒＹ＞ｔ＞Ｊ／Ｉ（１１０／ｏ）Ｃ−５
キトプンの謬り｛（吏ｔ’／．）
Ｃ−５ 代’ｒＹ ン＊＝Ｋ，ｔ（ｔｔ’／ｏ）第５
図
（Ａ）
（Ｂ）
トリアムレノロン
薄ム吟Ｍ（今）
（Ｃ）
プしド゛ニゾロン
５容広崎ｒ４（分）
溶よ叶間（分）
第５図
（Ｅ）
（Ｆ）
ジ゛コ゛Ａ冫ノ
溶二杵間（分）
ＣＧ）
フェシトイン
噌云崎間（分）
第６図
（Ａ）
７ルルどプロフェン
物理Ｉ１９逢合物
固イ４ζ分乍し（イニド、
ＣＢ）
インドノタンン
物環的混／？Ｆ物
ｉイネ分散イイ（
２ｅ（＠）
（Ａ）
′Ａｓ．
（″′Ｃ）
第６図
（Ｃ）
ジゴ〜シン
尋脣１的４７外旬
（Ｄ）
ドリア４ンノＯン
物惺的』し分物
ロ０イ爪分】じ（イ戚
２θ（＠）
ＣＢ）
インドメタシン
五度（゜Ｃ）
叙ム早（ｉｔ’／．）／ １梱Ｏ竺剤
手続補正書
平成１年１２月１５日
１．事件の表示
昭和６３年特許願第２８５５６６号
２．発明の名称
薬剤組成物
３．補正をする者
事件との関係 特許出願人
住 所 熊本県熊本市長嶺町１６７５番地３２氏名
小田切優樹
住 所 熊本県熊本市花立二丁目２５５番地氏名
今井輝子
代表者
４．代理人
住所
代表取締役社長 高岡 清
〒１０５ 電話４３６−４７００
東京都港区西新橋３丁目１５番８号
訂正明細書
１．発明の名称
薬剤組成物
２．特許請求の範囲
（１）低分子量キトサンと難溶性薬剤とを含有する薬剤
組成物．
３．発明の詳細な説明
〔産業上の利用分野〕
本発明は、低分子量キトサンと難溶性薬剤とを含有する
薬剤組成物に関する。
〔従来の技術〕
一般に、難溶性医薬品と称される医薬品は水に対する溶
解性が極めて悪く、従って生体に経口投与した場合の吸
収速度が遅く、絶対的な吸収量も少ない場合が多い。従
って難溶性医薬品を水に溶け易くするために塩酸塩やナ
トリウム塩といった塩の形にしたり、水溶性のプロドラ
ッグにする試みがなされている．また製剤的見地から、
界面活性剤のような可溶化剤を添加したり、サイクロデ
キストリン等で包接化する試みがなされている．また結
晶レベルでは、原末を微粉化したり，非品質化したりす
る試みがなされている．
しかし、これらの従来技術は医薬品それぞれで有効な方
法が異なるため、すべての医薬品に有効な方法とは言い
難く、特に難溶性医薬品の絶対的な吸収量を改善できて
も，必ずしも吸収速度の改善はできないのが現状である
。ところが、難溶性医薬品の中にはその薬理効果の面か
ら速効性を期待される医薬品も多く含まれており，吸収
量の面からのみではなく、吸収速度の面からも良好な経
口投与製剤が望まれている．
このような状況の中で、戴溶性薬剤の吸収性の改善に種
々の高分子を利用することが検討されている．
高分子量のゼラチンを利用する方法として、特開昭５７
−２６６１５号には，難溶性薬剤と高分子量のゼラチン
等を共粉砕する方法が記載されている。しかし、この方
法は難溶性薬剤の吸収改善のために添加するゼラチン量
が多く、また製造法も共粉砕法に−謬られているという
欠点がある．一方、カニやエビの甲殻から得られるキチ
ンやキトサンを製剤に利用する試みもなされている．と
ころが、キチンやキトサンの利用は、薬剤の徐放化の目
的で検討されているのが大部分であり、難溶性薬剤の可
溶化に関するものはまだ少ない．特公昭６３−２８４１
４号には、キチンおよび／またはキトサンと、抗生物質
および抗てんかん剤から選ばれるいずれか１種の難溶性
薬剤とを、薬剤の大部分が非結晶化する程度に混合共粉
砕し、薬剤の吸収速度および吸収量を改善する方法が記
載されている．しかし、この方法は、低分子量のキトサ
ンを開示しておらず、また混合共粉砕には多大な時間と
動力を要するとともに、製剤工程が複雑化するという問
題点がある。
また、キタサマイシンと各種高分子化合物とをロール混
合することにより、キタサマイシンの溶解速度を向上さ
せる方法が報告されており〔表面、２６（５）３３６（
１９８８）） ．この中でキトサンは酢酸塩溶液として
用いるが、ポリビニルピロリドンの効果に比較すると劣
ったものとなっている。
〔発明が解決しようとする課題〕
本発明の目的は、上記のような問題点を解決するため、
種々の難溶性薬剤の水に対する溶解度と溶出速度が改善
された薬剤組成物を提供することである。さらに、湿式
法、乾式法、共粉砕法、噴霧造粒法等の種々の製剤法に
より種々の形態に製剤化できる難溶性薬剤を含有する薬
剤組成物を提供することである。
〔課題を解決するための手段〕
本発明者らは、難溶性医薬品の水に対する溶解性改善の
ために、種々の高分子の添加効果を検討してきた。その
結果、低分子量キトサンと忽溶性薬剤とを混合すること
により、難溶性薬剤の溶解度と溶出速度が改善されるこ
とを発見し本発明を完成した。
すなわち、本発明は、低分子景キトサンと難溶性薬剤と
を含有する薬剤組成物である。
本発明の薬剤組成物は、種々の難溶性医薬その他の薬剤
の溶解度と溶出速度を改善するために利用でき、これら
の難溶性薬剤の生体内への吸収速度および吸収量が改善
された医薬品その他の薬剤組成物として利用できる。
本発明で使用する低分子量キトサンは、天然のキチンか
ら得られるキトサンの低分子化物であり、重量平均分子
量が５００〜ｓｏ ｘ ｔｏ３．好ましくは８００〜１
０ Ｘ １０３で、酸性はもちろん，中性ないしアルカ
リ性の水に溶解するキトサンである．重景平均分子景が
５００未満の場合およびｂｏ ｘ ｔｏ’を超える場合
は，難溶性薬剤の溶解度と溶出速度の改善効果が小さく
なる。重量平均分子量は、ゲルパーミ工一ションク口マ
トグラフィーにより分子量既知のポリエチレングリコー
ルを＠３準として決定できる。
低分子量キトサンの原料となるキトサンは、カニやエビ
の甲殻などからキチンを取り出し、アルカリで脱アセチ
ル化することにより得られる高分子物質である。この場
合のキトサンの脱アセチル化の程度は特に限定されるも
のではなく、酸性水溶液に可溶な範囲であればよく、一
般的には５０〜１００％である。 このようなキトサン
から低分子量キトサンを得るには、キトサンに酵素を作
用させる酵素的方法、あるいはキトサンに過酸化水素、
亜硝酸イオン、アルカリ，酸などを加えてグルコシド結
合を切断する化学的方法により、低分子量キトサンを得
ることができる。
化学的方法により低分子量キトサンを得るには、キトサ
ンをアルカリ液中に懸濁させ、適量の過酸化水素を添加
して一定温度下に一定時間反応させ低分子化し、その後
説塩，分子量分画等の精製を行い、水分除去後乾燥して
粉末化すればよい。このような方法でキトサンを切断し
低分子化する条件は、２１１６〜１２、過酸化水素濃度
ｏ．ｏｏｓ〜１０重量％，液温２０〜９０℃、反応時間
３０〜５００分程度が好ましい。
また酵素的方法によれば，キトサンとキチナーゼまたは
キトサナーゼとを接触させて低分子化する。その後上述
の方法で粉末化すればよい。
本発明において使用できる難溶性薬剤は難溶性医薬品が
例示され、その生体内への吸収速度あるいは吸収量（パ
イオアベイラビリテイ）が充分とは言えない医薬品であ
れば特に限定されない．このような医薬品としては、例
えば以下のものがあげられる．
１）催眠・鎮静剤：
例えば、ニトラゼパム，トリアゾラム、フェノバルビタ
ール、アモバルビタール等
２）抗で．んかん剤：
例えば、フェニトイン、メタルビタール、プリミドン、
クロナゼパム、カルバマゼピン，バルプ口酸等
３）解熱鎮痛消炎剤：
フルルビプロフエン、メフエナム酸、ケトプロフェン、
イブプロフェン．インドメタシン、ジクロフェナク酸、
フェナセチン、オキシフェンブタゾン、フエニルブタゾ
ン，スルピリン、ペンタゾシン，ピロキシカム等
４）鎮うん剤：
塩酸メクリジン、ジメンヒドリナート等５）精神神経用
剤：
ハロペリドール、メプロバメート、クロルジアゼポキシ
ド，ジアゼパム，オキサゼバム、スルビリド等
６）鎮けい剤：
パパベリン、アトロビン、エトミドリン等７）強心剤：
ジゴキシン、ジギトキシン、メチルジゴキシン、ユビデ
カレノン等
８）不整脈用剤：
ビンドロール、アジマリン、ジソピラミド等９）利尿剤
：
ヒドロクロロチアジド，スビロノラクトン、トリアムテ
レン、フロセミド、ブメタニド等１０）抗高血圧剤：
レセルビン、メシル酸ジヒドロエルゴトキシン，塩酸プ
ラゾシン、メトプロロール、プロプラノロール、アテノ
ロール等
１１）冠血管拡張剤：
ニトログリセリン、硝酸イソソルビド、ジルチアゼム、
ニフェジピン，ジビリダモール等１２）鎮咳剤：
ノス力ピン、サルブタモール、プロ力テロール，ツロプ
テロール，トラニラスト、ケトチフェン等
１３）脳循環改善剤：
ニカルジピン、ピンポセチン等
１４）抗生物質：
エリスロマイシン、ジョサマイシン、クロラムフェニコ
ール，テトラサイクリン、リファンピシン、グリセオフ
ルビン等
１５）抗ヒスタミン剤：
ジフェンヒドラミン，プロメタジン，メキタジン等
１６）ステロイド剤：
トリアムシノロン、デキサメサゾン、ベタメサゾン、プ
レドニゾロン、ダナゾール，メチルテストステロン，酢
酸クロルマジノン等１７）ビタミン剤：
ビタミンＥ、ビタミンＫ、アルファ力ルシドール、フィ
トナジオン，ニコチン酸ｄトα一トコフェロール、メナ
テトレノン等
１８）その他：
ジクマロール，シンナリジン、クロフィブラート、ゲフ
ァルナート，シメチジン、プロベネシド、メルカプトプ
リン、メトトレキサート、ウルソデスオキシコール酸、
メシル酸ジヒドロエルゴタミン等
上記の難溶性医薬品は原末の溶解性の面から，湿式また
は乾式の粉砕機で粉砕して得られる平均粒径１００μｍ
以下、好ましくは５０μｍ以下であることが望ましい。
本発明の薬剤組成物は低分子量キトサンと難溶性薬剤と
を混合することにより得られる。混合に際しては、低分
子量キトサンを離溶性薬剤に対して均一に分散させるの
が望ましい。混合方法は特に限定されず、例えば粉末状
の両成分を単純に混合する方法（以下、このような方法
で得られた組成物を物理的混合物という。）、粉末状の
両成分に適当量の水等の溶媒を添加して混棟する方法（
以下、このような方法で得られた組成物を固体分散体と
いう。）、低分子量キトサン水溶液中に難溶性薬剤を添
加する方法などをあげることができる．混合に際し、低
分子量キトサンは、混合する難溶性薬剤の種類により適
宜量使用すればよい．一般的には、難溶性薬剤１重量部
に対して低分子量キトサンを０．２〜１０重量部配合す
れば，難溶性薬剤の溶解度と溶出速度を改善することが
できる．本発明の薬剤組成物は、種々の方法により製剤
化してヒトに投薬することができる．すなわち，本発明
の薬剤組成物は、そのまま顆粒剤として用いることがで
きるし、錠剤、カプセル剤，軟膏、貼布剤、座剤，シロ
ップ剤、トローチ剤などとして用いることもできる．こ
れらの製剤中には必要に応じて製剤上知られる賦形剤，
崩壊剤，滑沢剤等の種々の添加剤を配合することができ
る６本発明の薬剤組成物は、次のような方法で製剤化す
ることができる。錠剤は、低分子量キトサンと難溶性薬
剤とを水、酸溶液あるいは適当な溶媒を用いて練合し，
乾燥，整粒、打錠を行う練合法、低分子量キトサンと難
溶性薬剤とを練合し、乾燥，整粒後，種々の添加剤を混
合し、打錠を行う半直打法などの湿式法、低分子量キト
サンの量を調整することにより乾式法あるいは共粉砕法
等により製造することができる．これらの中では湿式法
により固体分散体とするのが好ましい．顆粒剤およびカ
プセル剤においても錠剤の場合と同様に湿式法により製
剤化するのが好ましいが、場合によっては乾式法や共粉
砕法あるいは噴霧造粒法等も採用することができる。ま
た、錠剤および顆粒剤などの剤形においては、マスキン
グ等の目的でコーティングを施すこともできる。
以上のようにして製造した製剤は，従来のものに比べて
難溶性薬剤の溶解度と溶出速度が改善されているため、
パイオアベイラビリティの良好な医薬品となる．
〔発明の効果〕
本発明によれば，難溶性薬剤を低分子量キトサンと配合
するようにしたので、難溶性薬剤の水に対する溶解度と
溶出速度が改善された薬剤組成物を得ることができる．
また、この薬剤組成物は湿式法、乾式法、共粉砕法、噴
霧造粒法等の種々の製剤法により種々の形態に製剤化で
きる．さらに本発明の薬剤組成物からなる医薬品は、難
溶性薬剤の生体内への吸収速度および吸収量が改善され
た医薬品となる。
〔実施例〕
次に、本発明の実施例について説明する．各例中、％は
重量％を示す．
参考例１
紅ずわいがにから常法によりキトサンを得た（以下、Ｃ
−０と略記する）． このキトサンを水に懸濁させ，
ｐＨ１１．０、温度を７０℃に保ち、攪拌しながら過酸
化水素水を過酸化水素として２．１〜４０．０ｇＩＱ添
加して． １１０〜３００分間反応させて低分子化した
．低分子化した後脱塩精製し、次いで凍結乾燥し、第１
表に示す低分子量キトサンＣ−１、Ｃ−２． Ｃ−３お
よびＣ−４を得た．また、同様にキトサン（Ｃ−Ｏ）を
ＰＩ｛８．０、温度を７０℃に保ち、攪拌しながら過酸
化水素水を過酸化水素として４０ｇ＃ｌ添加して低分子
化した．低分子化後濾過により固形分を除き、次いでＵ
Ｆ膜を用いて分子量分画を行い、凍結乾燥して低分子量
キトサンＣ−５を得た．
このようにして得たキトサンの物性を第１表に示す。第
１表中の蒸発残分は、１０５℃で乾燥させた時の残渣で
あり、灰分は６００℃で燃焼した時の残渣である。キト
サンの分子量は、ゲルパーミエーションク口マトグラフ
ィーで測定した．すなわちキトサンを同量の酢酸と適当
量の水を用いて溶解し、この溶液２．Ｏｍｆｌを０．２
Ｍ酢酸−０．１阿酢酸ナトリウム緩衝液で５０ｍＭとし
、これを東ソー（株）製のＴＳＫ Ｇｅｌ． ３０００
ＰＶＸＬ（商標）からなる充填力ラムに注入し、０．
２Ｍ酢酸−０．１Ｍ酢酸ナトリウム緩衝液で溶出した．
なお、分子量既知のポリエチレングリコールを用いて較
正曲線を求め、キトサンの重量平均分子量を求めた．
第１表
実施例１
参考例１で得たＣ−０ないしＣ−５のキトサンとフルル
ビプロフエン（以下、ＦＰと略記する場合がある）とを
重量比１：１の割合で秤量し，キトサンの２倍量の水を
添加して１時間混練した．室温減圧下４８時間乾燥し、
１００メッシュ以下の粒子を固体分散体とした。この固
体分散体について、３７℃の水中におけるＦＰの溶出速
度を下記の方法で測定した．３７℃に保った溶出試験器
（富山産業（株）製溶出試験器）に水５００ｍＱを入れ
、上記の固体分散体をＦＰとして４０ｍｇ相当量加え，
９１ｒｐｍで攪拌した．一定時間毎に綿栓付きピペット
で試料溶液を３鳳Ｑ採取し、０．４５４メンプランフィ
ルターでろ過し、ろ液のＦＰ濃度をクロロホルムで抽出
して定量した．結果を第１図に示す．
実施例２
ビタミンＥまたはビタミンＫと低分子量キトサンＣ−５
との組成物を下記の方法で調製し、ビタミンＥまたはビ
タミンＫの溶解度を下記の方法で測定した．
一定過剰量のビタミンＥまたはビタミンＫを５ｍｇ精秤
して試験管に取り，種々の濃度の参考例１で得たＣ−５
のキトサン水溶液を加えて密栓し，２５℃で１０日間振
盪した．溶解平衡に達した各飽和溶液を綿栓付きピペッ
トで採取し、０．４５μｍメンプランフィルターでろ過
し、クロロホルムで抽出してＵｖ法によりビタミンＥま
たはビタミンＫの濃度を定量した．
ビタミンＥの結果を第２図、ビタミンＫの結果を第３図
に示す．
実施例３
第２表に示す難溶性薬剤と低分子量キトサンＣ一５との
組成物について，実施例２と同様にして各薬剤の溶解度
を測定した．結果をまとめて第４図（Ａ）〜（シ）に示
す．
第２表
第４図から分るように、各薬剤の溶解度は低分子量キト
サンの濃度上昇とともに上昇した．特に酸性薬剤の場合
に著しい上昇が［察された。これは塩基性多糖である低
分子量キトサンと酸性薬剤との対イオン形成等の相互作
用が関与しているものと考えられるが，薬剤の解離をあ
まり考慮しなくても良いステロイド剤であるジゴキシン
およびフェニトインの場合にも溶解度が上昇した．また
、ベタメサゾンおよびトリアムシノロンの場合には薬剤
の溶解度の上昇部分、プラト一部分および下降曲線部分
を伴うＢ５型相図を与えた．これらの結果は，低分子量
キトサンが各薬剤と単に対イオンを形成するだけでなく
、何らかの相互作用をすることにより薬剤の溶解度を上
昇させているものと推定される。
実施例４
トリアムシノロン、ベタメサゾン、プレドニゾロン，フ
ルルビプロフェン、インドメタシン、ジゴキシンおよび
フェニトインの各薬剤の固体分散体と薬剤単独物につい
て溶出速度を測定した．測定方法は，参考例１で得た低
分子量キトサンＣ−５を用いて、実施例１と同様（但し
、薬剤は１０〜３０ｍｇ相当量加え、溶出液６０ｍ（ｌ
を５７ｒｐｍで撹拌した）にして一定時間毎に薬剤の溶
出濃度を測定し、薬剤の溶出割合（全添加量に対する溶
出量）を算出した。結果をまとめて第５図（Ａ）〜（Ｇ
）に示す。
なお，フルルビプロフェンの結果については，再掲載す
る。
さらに、溶出速度から算出した平均溶出時間を第３表に
示す。なお平均溶出時間の算出はｃｈｅ＋ｏ．ｐｈａｒ
ｍ． Ｂｕｌｌ．， Ｖｏｌ ３０， ｐｌ０８８ （
１９８２）の方法によった・
第３表
いずれの薬剤においても、固体分散体からの薬剤の溶出
速度は薬剤単独の場合に比べて著しく速くなった。酸性
薬剤の場合には、実施例３の結果から明らかなように，
薬剤の溶解度上昇に伴う溶出速度の増大が考えられるが
、溶解度の上昇があまり認められなかった薬剤において
も著しい溶出速度の増大が観察された。
実施例５
フルルビプロフェンと参考例１で得た低分子量キトサン
Ｃ−５の粉末を重量比１：３の割合で単純に混合して得
た物理的混合物と，フルルビプロフェンとＣ−５の配合
割合を重量比１：３に代えた以外は実施例１と同様にし
て得た固体分散体について、粉末Ｘ線回折を行った。粉
末Ｘ線は理学電気■製Ｇｅｉｇｅｒ Ｆｌｅｘ ２１０
２ Ｘ線回折装置を使用し、Ｃｕ−Ｋａ線、Ｎｉフィル
ターを用い， ３０ｋＶ、２０ｍＡ、時定数２ｓｅｃ、
走査速度１℃／’ｍｉｎで測定した。
インドメタシン、ジゴキシン、トリアムシノロンについ
ても上記と同様にして粉末Ｘ線回折を行った。結果を第
６図（Ａ）〜（Ｄ）に示す。
粉末Ｘ線回折パターンは薬剤の結晶系および充填状態に
関する情報を与える。第６図（Ａ）〜（Ｄ）から分るよ
うに、低分子量キトサン単独は非品質性物質であるため
、物理的混合物の場合には薬剤特有の特性ピークが観察
された。酸性薬剤のフルルビプロフェンの場合には、物
理的混合物で観察された薬剤の特性ピークが固体分散体
では観察されず、フルルビプロフェンが低分子量キトサ
ン中に非品質化して分散していることを示した。一方他
の３つの薬剤の固体分散体は物理的混合物と全く同じ回
折パターンを示し，低分子量キトサン添加による薬剤の
結晶性の低下は認められなかった。
実施例６
融点が低分子量キトサンより低いフルルビプロフェンと
インドメタシンについて示差熱量を測定した．測定に使
用した試料は，実施例５で得た物理的混合物、固体分散
体、低分子漱キトサン単独物、薬剤単独物である．示差
熱量は、理学電気■製Ｔｈｅｒｍｏｆｌｅｘ ＴＧ−８
１１０を使用し、試料は薬剤単独として５１ｍｇを昇温
速度ｌＯ℃／ｆｆｉｉｎで、α−アルミナを標準物質に
用いて測定した。結果を第７図（Ａ）、（Ｂ）に示す。
示差熱量は，薬剤の融解に基づく吸熱ピークを観察する
ことにより、固体中の薬剤の状態を知ることができる。
第７図から分るように、フルルビブロフェンの固体分散
体の場合には、薬剤の融解に基づくピークが消失し、フ
ルルビプロフエンが低分子量キトサンとの固体分散体中
に結晶性を失って分散していることを示した．一方イン
ドメタシンの場合には、固体分散体においても薬剤の融
解ピークがみられ，インドメタシンは結晶性を保ったま
ま固体分散体中に分散していることを示した。これらの
結果は実施例５の結果と一致しており、フルルビプロフ
エンは低分子景キトサンと固体状態において何らかの相
互作用をして，低分子景キトサンとの固体分散体中に非
晶質化して存在するが、他の薬剤は低分子量キトサンと
ほとんど相互作用せずに，結晶性を有したまま固体分散
体中に存在することが推定される。
実施例７
フルルビプロフエン、インドメタシン、およびトリアム
シノロンについて薬剤粒子表面のぬれを測定した．測定
に使用した試料は、実施例５で得た固体分散体と薬剤単
独物である。ぬれはＩＲ打錠機により直径２ｃｍの錠剤
を成形し、その表面に５０一の水を落して、接触角を測
定することにより求めた。結果を第４表に示す．
第４表
第４表から分るように、薬剤単独の接触角に比べて、低
分子量キトサンとの固体分散体のそれは低下した。これ
らの結果から低分子量キトサンは薬物粒子表面水に対す
るぬれを改善することにより溶出速度を上昇させるもの
と推定される。
実施例８
フルルビプロフェンと、参考例１で得た低分子量キトサ
ンＣ−２、Ｃ−４またはＣ−５との混練体（重景比で１
：１または１：５）からＨ−１５ （カカオ油脂）を基
剤として坐剤をつくり、この坐剤からのフルルビプロフ
ェンの放出率を測定した。結果を第８図に示す。FIG. 1 is a graph showing the results of Example 1, FIGS. 2 and 3 are graphs showing the results of Example 2, and FIGS.
L) is a graph showing the results of Example 3, Figures 5(A) to (
G) is a graph showing the results of Example 4, and FIGS. 6(A) to (
D) is a graph showing the results of Example 5, FIG. 7(A).
(B) is a graph showing the results of Example 6, and FIG. 8 is a graph showing the results of Example 8. Figure 1 S Koginma (minutes) Agent Patent Attorney Sei Yanagihara Figure 2 Figure 4 (A) CB) C-5 It'n》 Figure 3 C-5 Betopn 05 Izumi J (.11/.) C-5
Betopun no Su/t (it'/JC-5 Sotobunrichi la<v amount 0l0) Fig. 4 Fig. 4 (E) (F) C-5 Motopunorishi Guest, 1 (-1t°/.) C-5
Sakaishi % (weight.t'/.)C-5N}bu>n
J/t (Sumire t'/.)C-5 Daitobun Archer/l(
Sumire 10I0) (G) (H) C-5 Hedobuntsuzo L degree (Satoko 010) C-5
'r'rY>t>J/I (110/o) C-5 Kitopun's fallacy {(吏t'/.) C-5 'rY N*=K,t(tt'/o) No. 5
Figures (A) (B) Triamrenolone thin volume M (now) (C) Nizoron 5 volume Hirosaki r4 (minutes) Soluyokanama (minutes) Figure 5 (E) (F) Ziko A CG) Fecytoin Sounsaki time (minutes) Figure 6 (A) 7 luldoprofen physics I19 mixture solidity 4 ζ minutes (inide, CB) ? F thing i rice dispersion good (2e(@) (A) 'As. ('''C) Fig. 6 (C) Jigo ~ Shin 1st 47 out of season (D) Doria 4 n no O on thing s.'' Shibunmonoro 0i Tsumebun】ji (Irami2θ (@) CB) Indomethacin 5th degree (゜C) It'／.／ 1st package O-filter procedure amendment December 15, 1999 Day 1. Indication of the case Patent Application No. 285566 filed in 1985 2. Name of the invention Pharmaceutical composition 3. Person making the amendment Relationship to the case Patent applicant address Name 32, 1675 Nagamine-cho, Kumamoto, Kumamoto Prefecture
Yuki Odagiri Address 2-255 Hanatate, Kumamoto City, Kumamoto Prefecture Name
Representative Teruko Imai 4. Agent Address Representative Director and President Kiyoshi Takaoka Address: 105 Telephone: 436-4700 3-15-8 Nishi-Shinbashi, Minato-ku, Tokyo Amended Statement 1. Title of the invention Pharmaceutical composition 2. Claims (1) A pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug. 3. DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug. [Prior Art] In general, pharmaceuticals called poorly soluble pharmaceuticals have extremely poor solubility in water, and therefore, when orally administered to a living body, the rate of absorption is slow and the absolute amount absorbed is often small. Therefore, attempts have been made to make poorly soluble drugs more soluble in water by converting them into salt forms such as hydrochloride or sodium salt, or by making them water-soluble prodrugs. Also, from a pharmaceutical standpoint,
Attempts have been made to add solubilizers such as surfactants or to clathrate them with cyclodextrins. Furthermore, at the crystal level, attempts are being made to pulverize or degrade the bulk powder. However, these conventional techniques have different effective methods for each drug, so it is difficult to say that they are effective methods for all drugs.Even if the absolute absorption amount of poorly soluble drugs can be improved, it does not necessarily improve the absorption rate. The current situation is that this is not possible. However, there are many poorly soluble drugs that are expected to be fast-acting due to their pharmacological effects, and it is important to find oral preparations that are good not only in terms of amount absorbed but also in terms of absorption speed. It is desired. Under these circumstances, the use of various polymers to improve the absorption of soluble drugs is being investigated. As a method of using high molecular weight gelatin, JP-A-57
No. 26615 describes a method of co-pulverizing a poorly soluble drug and high molecular weight gelatin. However, this method has the disadvantage that a large amount of gelatin is added to improve the absorption of poorly soluble drugs, and the manufacturing method is also based on the co-pulverization method. On the other hand, attempts have also been made to use chitin and chitosan obtained from crab and shrimp shells in pharmaceutical preparations. However, most of the uses of chitin and chitosan have been investigated for the purpose of sustained release of drugs, and there are still few studies on the use of chitin and chitosan for solubilizing poorly soluble drugs. Tokuko Showa 63-2841
In No. 4, chitin and/or chitosan and any one kind of poorly soluble drug selected from antibiotics and antiepileptic drugs are mixed and co-pulverized to such an extent that most of the drug becomes amorphous. Methods to improve absorption rate and amount are described. However, this method does not disclose low-molecular-weight chitosan, and there are problems in that mixing and co-pulverization requires a great deal of time and power, and the formulation process becomes complicated. In addition, a method has been reported for improving the dissolution rate of kitasamycin by roll-mixing kitasamycin and various polymer compounds [Surface, 26(5) 336 (
1988)). Among these, chitosan is used as an acetate solution, but its effectiveness is inferior to that of polyvinylpyrrolidone. [Problems to be Solved by the Invention] The purpose of the present invention is to solve the above-mentioned problems.
An object of the present invention is to provide a drug composition in which the water solubility and dissolution rate of various poorly soluble drugs are improved. Another object of the present invention is to provide a pharmaceutical composition containing a poorly soluble drug that can be formulated into various forms by various formulation methods such as a wet method, a dry method, a co-pulverization method, and a spray granulation method. [Means for Solving the Problems] The present inventors have investigated the effects of adding various polymers to improve the solubility of poorly soluble pharmaceuticals in water. As a result, the present invention was completed by discovering that the solubility and dissolution rate of a poorly soluble drug can be improved by mixing low molecular weight chitosan with a slowly soluble drug. That is, the present invention is a pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug. The pharmaceutical composition of the present invention can be used to improve the solubility and dissolution rate of various poorly soluble drugs and other drugs, and can be used to improve the solubility and dissolution rate of various poorly soluble drugs and other drugs, and can be used to improve the absorption rate and amount of these poorly soluble drugs into the body. It can be used as a pharmaceutical composition. The low molecular weight chitosan used in the present invention is a low molecular weight chitosan obtained from natural chitin, and has a weight average molecular weight of 500 to 3. Preferably 800-1
0 x 103, chitosan is soluble in acidic as well as neutral to alkaline water. If the weighted average molecular weight is less than 500 or exceeds box x to', the effect of improving the solubility and dissolution rate of poorly soluble drugs will be reduced. The weight average molecular weight can be determined by gel permeability chromatography using polyethylene glycol of known molecular weight as @3 standard. Chitosan, which is the raw material for low-molecular-weight chitosan, is a polymeric substance obtained by extracting chitin from crab and shrimp shells and deacetylating it with alkali. The degree of deacetylation of chitosan in this case is not particularly limited, and may be within a range that is soluble in an acidic aqueous solution, and is generally 50 to 100%. In order to obtain low molecular weight chitosan from such chitosan, an enzymatic method in which chitosan is treated with an enzyme, or chitosan is treated with hydrogen peroxide,
Low molecular weight chitosan can be obtained by a chemical method in which nitrite ions, alkalis, acids, etc. are added to cleave glucoside bonds. To obtain low-molecular-weight chitosan by a chemical method, chitosan is suspended in an alkaline solution, an appropriate amount of hydrogen peroxide is added, the reaction is carried out at a certain temperature for a certain period of time, and the molecular weight is reduced. After removing moisture, it may be dried and powdered. The conditions for cleaving chitosan and reducing its molecular weight by such a method are: 2116-12, hydrogen peroxide concentration o. oos to 10% by weight, liquid temperature of 20 to 90°C, and reaction time of about 30 to 500 minutes. According to the enzymatic method, chitosan is brought into contact with chitinase or chitosanase to reduce the molecular weight. Thereafter, it may be pulverized by the method described above. The poorly soluble drug that can be used in the present invention is exemplified by a poorly soluble drug, and is not particularly limited as long as the drug has insufficient absorption rate or amount (bioavailability) into the body. Examples of such drugs include the following: 1) Hypnotic and sedative agents: For example, nitrazepam, triazolam, phenobarbital, amobarbital, etc. 2) Antibiotics. Depressants: For example, phenytoin, metalbital, primidone,
Clonazepam, carbamazepine, bulp acid, etc. 3) Antipyretic, analgesic and anti-inflammatory agents: flurbiprofen, mefenamic acid, ketoprofen,
Ibuprofen. indomethacin, diclofenacic acid,
Phenacetin, oxyphenbutazone, phenylbutazone, sulpirin, pentazocine, piroxicam, etc. 4) Antidepressants: meclizine hydrochloride, dimenhydrinate, etc. 5) Neuropsychiatric agents: haloperidol, meprobamate, chlordiazepoxide, diazepam, oxazebam, sulviride, etc. 6) Antidepressants: Spuratives: papaverine, atronolactone, etomidrine, etc. 7) Inotropes: digoxin, digitoxin, methyldigoxin, ubidecarenone, etc. 8) Antiarrhythmic agents: vindolol, ajmaline, disopyramide, etc. 9) Diuretics: hydrochlorothiazide, subironolactone, triamterene, furosemide, bumetanide, etc. 10 ) Antihypertensive agents: Reservin, dihydroergotoxin mesylate, prazosin hydrochloride, metoprolol, propranolol, atenolol, etc. 11) Coronary vasodilators: Nitroglycerin, isosorbide nitrate, diltiazem,
Nifedipine, diviridamol, etc. 12) Antitussives: Nosiropin, salbutamol, proterol, tulopterol, tranilast, ketotifen, etc. 13) Cerebral circulation improving agents: Nicardipine, pinpocetine, etc. 14) Antibiotics: Erythromycin, josamycin, chloramphenicol, tetracycline , rifampicin, griseofulvin, etc. 15) Antihistamines: diphenhydramine, promethazine, mequitazine, etc. 16) Steroids: triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate, etc. 17) Vitamins: vitamin E, vitamin K, alpha-lucidol , phytonadione, alpha-tocopherol nicotinate, menatetrenone, etc. 18) Others: dicoumarol, cinnarizine, clofibrate, gefarnate, cimetidine, probenecid, mercaptopurine, methotrexate, ursodesoxycholic acid,
The above-mentioned poorly soluble drugs such as dihydroergotamine mesylate have an average particle size of 100 μm when ground with a wet or dry grinder due to the solubility of the bulk powder.
Hereinafter, it is preferably 50 μm or less. The pharmaceutical composition of the present invention can be obtained by mixing low molecular weight chitosan and a poorly soluble drug. During mixing, it is desirable that the low molecular weight chitosan be uniformly dispersed in the dissolvable drug. The mixing method is not particularly limited, and examples include a method of simply mixing both powdered components (hereinafter, a composition obtained by such a method is referred to as a physical mixture), a method of simply mixing both powdered components, and a method of mixing an appropriate amount of both powdered components. Method of mixing by adding a solvent such as water (
Hereinafter, the composition obtained by such a method will be referred to as a solid dispersion. ), methods of adding poorly soluble drugs to low molecular weight chitosan aqueous solutions, etc. When mixing, low molecular weight chitosan may be used in an appropriate amount depending on the type of poorly soluble drug to be mixed. Generally, by blending 0.2 to 10 parts by weight of low molecular weight chitosan to 1 part by weight of a poorly soluble drug, the solubility and dissolution rate of the poorly soluble drug can be improved. The pharmaceutical composition of the present invention can be formulated and administered to humans by various methods. That is, the pharmaceutical composition of the present invention can be used as granules as is, or can be used as tablets, capsules, ointments, patches, suppositories, syrups, troches, etc. These formulations may contain excipients known in the formulation, as necessary.
6 The pharmaceutical composition of the present invention, which can contain various additives such as a disintegrant and a lubricant, can be formulated by the following method. Tablets are made by kneading low-molecular-weight chitosan and a poorly soluble drug using water, an acid solution, or an appropriate solvent.
Wet methods include a kneading method that involves drying, sizing, and tableting, and a semi-direct compression method that involves kneading low-molecular-weight chitosan and a poorly soluble drug, drying, sizing, mixing various additives, and then compressing into tablets. It can be produced by dry method or co-pulverization method by adjusting the amount of low molecular weight chitosan. Among these, it is preferable to form a solid dispersion using a wet method. Granules and capsules are preferably formulated by a wet method as in the case of tablets, but depending on the case, dry methods, co-pulverization methods, spray granulation methods, etc. may also be employed. In addition, dosage forms such as tablets and granules may be coated for purposes such as masking. The preparations produced as described above have improved solubility and dissolution rate of poorly soluble drugs compared to conventional preparations.
It is a drug with good bioavailability. [Effects of the Invention] According to the present invention, since a poorly soluble drug is blended with low molecular weight chitosan, it is possible to obtain a drug composition in which the water solubility and dissolution rate of the poorly soluble drug are improved.
Moreover, this pharmaceutical composition can be formulated into various forms by various formulation methods such as wet method, dry method, co-pulverization method, and spray granulation method. Furthermore, a pharmaceutical composition comprising the pharmaceutical composition of the present invention is a pharmaceutical product in which the rate and amount of poorly soluble drug absorbed into the body are improved. [Example] Next, an example of the present invention will be described. In each example, % indicates weight %. Reference Example 1 Chitosan was obtained from red snow crab by a conventional method (hereinafter referred to as C
(abbreviated as -0). This chitosan is suspended in water,
While maintaining the pH at 11.0 and the temperature at 70°C, add 2.1 to 40.0 g IQ of hydrogen peroxide solution while stirring. The mixture was reacted for 110 to 300 minutes to reduce the molecular weight. After reducing the molecular weight, it is desalted and purified, then freeze-dried, and the first
Low molecular weight chitosan C-1, C-2 shown in the table. C-3 and C-4 were obtained. Similarly, chitosan (C-O) was kept at PI{8.0 and temperature at 70° C., and 40 g #l of hydrogen peroxide was added while stirring to reduce the molecular weight. After reducing the molecular weight, the solid content is removed by filtration, and then U
Molecular weight fractionation was performed using F membrane and freeze-dried to obtain low molecular weight chitosan C-5. The physical properties of the chitosan thus obtained are shown in Table 1. The evaporation residue in Table 1 is the residue when dried at 105°C, and the ash is the residue when burned at 600°C. The molecular weight of chitosan was determined by gel permeation chomatography. That is, chitosan is dissolved using the same amount of acetic acid and an appropriate amount of water, and this solution 2. Omfl 0.2
M acetic acid-0.1 sodium acetate buffer solution was adjusted to 50 mM, and this was added to TSK Gel. 3000
Inject into a filling force ram made of PVXL™ and set to 0.
Elution was performed with 2M acetic acid-0.1M sodium acetate buffer.
A calibration curve was obtained using polyethylene glycol of known molecular weight, and the weight average molecular weight of chitosan was determined. Table 1 Example 1 C-0 to C-5 chitosan obtained in Reference Example 1 and flurbiprofen (hereinafter sometimes abbreviated as FP) were weighed at a weight ratio of 1:1, Twice the amount of water as chitosan was added and kneaded for 1 hour. Dry at room temperature under reduced pressure for 48 hours,
Particles of 100 mesh or less were used as a solid dispersion. Regarding this solid dispersion, the elution rate of FP in water at 37°C was measured by the following method. 500 mQ of water was placed in a dissolution tester (dissolution tester manufactured by Toyama Sangyo Co., Ltd.) kept at 37°C, and an amount equivalent to 40mg of the above solid dispersion as FP was added.
Stirred at 91 rpm. Three sample solutions were collected at regular intervals using a pipette with a cotton stopper, filtered through a 0.454 membrane filter, and the FP concentration of the filtrate was extracted with chloroform and quantified. The results are shown in Figure 1. Example 2 Vitamin E or vitamin K and low molecular weight chitosan C-5
A composition was prepared using the method described below, and the solubility of vitamin E or vitamin K was measured using the method described below. Precisely weigh 5 mg of a certain excess amount of vitamin E or vitamin K, put it in a test tube, and prepare the C-5 obtained in Reference Example 1 at various concentrations.
An aqueous chitosan solution was added to the tube, the tube was sealed tightly, and the tube was shaken at 25°C for 10 days. Each saturated solution that had reached solubility equilibrium was collected using a pipette with a cotton stopper, filtered through a 0.45 μm membrane filter, extracted with chloroform, and the concentration of vitamin E or vitamin K was determined by the UV method. The results for vitamin E are shown in Figure 2, and the results for vitamin K are shown in Figure 3. Example 3 The solubility of each drug was measured in the same manner as in Example 2 for compositions of poorly soluble drugs and low molecular weight chitosan C-5 shown in Table 2. The results are summarized in Figures 4 (A) to (C). As can be seen from Table 2 and Figure 4, the solubility of each drug increased as the concentration of low molecular weight chitosan increased. A marked increase was observed, especially in the case of acidic drugs. This is thought to be related to the interaction between low molecular weight chitosan, which is a basic polysaccharide, and the acidic drug, such as the formation of counter ions. The solubility of phenytoin also increased. In addition, in the case of betamethasone and triamcinolone, a B5-type phase diagram with an increasing part, a plateau part, and a descending curve part of drug solubility was given. These results suggest that low-molecular-weight chitosan not only forms a counterion with each drug, but also interacts with it in some way to increase the solubility of the drug. Example 4 The dissolution rates were measured for solid dispersions of the drugs triamcinolone, betamethasone, prednisolone, flurbiprofen, indomethacin, digoxin, and phenytoin and for the drugs alone. The measurement method was the same as in Example 1 using the low molecular weight chitosan C-5 obtained in Reference Example 1 (however, the drug was added in an amount equivalent to 10 to 30 mg, and 60 ml (l) of the eluate was added.
(stirred at 57 rpm), the elution concentration of the drug was measured at regular intervals, and the elution ratio of the drug (the elution amount relative to the total amount added) was calculated. The results are summarized in Figure 5 (A) to (G).
). The results for flurbiprofen will be republished. Furthermore, the average elution time calculated from the elution rate is shown in Table 3. Note that the average elution time was calculated using che+o. phar
m. Bull. , Vol 30, pl088 (
1982) Table 3. For all drugs, the elution rate of the drug from the solid dispersion was significantly faster than that of the drug alone. In the case of acidic drugs, as is clear from the results of Example 3,
Although it is thought that the dissolution rate increases with an increase in the solubility of the drug, a significant increase in the dissolution rate was observed even for drugs for which no significant increase in solubility was observed. Example 5 A physical mixture obtained by simply mixing flurbiprofen and the low molecular weight chitosan C-5 powder obtained in Reference Example 1 at a weight ratio of 1:3, and a physical mixture of flurbiprofen and C-5 Powder X-ray diffraction was performed on a solid dispersion obtained in the same manner as in Example 1 except that the weight ratio of Example 5 was changed to 1:3. The powder X-ray is Geiger Flex 210 manufactured by Rigaku Denki.
2 Using an X-ray diffraction device, using Cu-Ka rays and a Ni filter, 30 kV, 20 mA, time constant 2 sec,
Measurement was performed at a scanning speed of 1° C./min. Powder X-ray diffraction was also performed on indomethacin, digoxin, and triamcinolone in the same manner as above. The results are shown in FIGS. 6(A) to (D). Powder X-ray diffraction patterns provide information regarding the crystal system and packing state of the drug. As can be seen from FIGS. 6(A) to 6(D), since low molecular weight chitosan alone is a non-quality substance, characteristic peaks unique to the drug were observed in the case of a physical mixture. In the case of the acidic drug flurbiprofen, the characteristic peaks of the drug observed in the physical mixture are not observed in the solid dispersion, indicating that flurbiprofen is dispersed in a non-qualified manner in low molecular weight chitosan. It was shown that On the other hand, the solid dispersions of the other three drugs showed exactly the same diffraction patterns as the physical mixtures, and no decrease in the crystallinity of the drugs was observed due to the addition of low molecular weight chitosan. Example 6 Differential calorific value was measured for flurbiprofen and indomethacin, which have lower melting points than low molecular weight chitosan. The samples used in the measurements were the physical mixture obtained in Example 5, the solid dispersion, the low-molecular soy chitosan alone, and the drug alone. The differential heat value is Thermoflex TG-8 manufactured by Rigaku Denki.
110, 51 mg of the drug alone was measured at a heating rate of 10° C./ffiin, and α-alumina was used as a standard substance. The results are shown in FIGS. 7(A) and (B). Differential calorific value allows the state of a drug in a solid to be determined by observing the endothermic peak due to melting of the drug. As can be seen from Figure 7, in the case of a solid dispersion of flurbibrofen, the peak due to the melting of the drug disappears, and flurbiprofen loses its crystallinity in the solid dispersion with low molecular weight chitosan. It was shown that the results are dispersed. On the other hand, in the case of indomethacin, a melting peak of the drug was observed even in the solid dispersion, indicating that indomethacin was dispersed in the solid dispersion while maintaining its crystallinity. These results are consistent with the results of Example 5, indicating that flurbiprofen has some kind of interaction with low molecular weight chitosan in the solid state and becomes amorphous in the solid dispersion with low molecular weight chitosan. However, it is presumed that other drugs exist in the solid dispersion while maintaining crystallinity, with little interaction with low molecular weight chitosan. Example 7 Wetting of drug particle surfaces was measured for flurbiprofen, indomethacin, and triamcinolone. The samples used in the measurement were the solid dispersion obtained in Example 5 and the drug alone. Wetting was determined by forming tablets with a diameter of 2 cm using an IR tablet press, dropping 50 mm of water onto the surface, and measuring the contact angle. The results are shown in Table 4. Table 4 As can be seen from Table 4, the contact angle of the solid dispersion with low molecular weight chitosan was lower than that of the drug alone. From these results, it is presumed that low molecular weight chitosan increases the dissolution rate by improving the wettability of the drug particle surface to water. Example 8 Kneaded product of flurbiprofen and low molecular weight chitosan C-2, C-4 or C-5 obtained in Reference Example 1 (1 in gravity ratio)
:1 or 1:5) to make suppositories using H-15 (cocoa oil and fat) as a base, and the release rate of flurbiprofen from these suppositories was measured. The results are shown in FIG.
第１図は実施例１の結果を示すグラフ，第２図および第
３図は実施例２の結果を示すグラフ，第４図（Ａ）〜（
Ｌ）は実施例３の結果を示すグラフ，第５図（Ａ）〜（
Ｇ）は実施例４の結果を示すグラフ、第６図（Ａ）〜（
Ｄ）は実施例５の結果を示すグラフ、第７図（Ａ）、（
Ｂ）は実施例６の結果を示すグラフ、第８図は実施例８
の結果を示すグラフである。
代理人 弁理士 柳 原 成
第２図
Ｃ−５ へトプンの沫度（ｔ量！ム）第３図
溶工吟間（分）
Ｃ−５版トプンつ濃／ｔ（ｉｔ’／．）第４図
第４図
（Ａ）
ＣＢ）
（Ｅ）
（Ｆ）
Ｃ−５−Ｎ｝プンの濃／Ｉ （ｔｔ ＠／ｏ）Ｃ−Ｓ
へトプ〉の濃，？（重，量．’／．）（Ｇ）
（Ｈ）
（−５ｘｔ４ンの５農度（ｉｔ’／．）Ｃ−５ 子ト
プンり濃／ｉＣｔ量’／．）Ｃ−Ｓ へトプンの儂／
Ｉ（！量０ｌ．）Ｃ−Ｓ 代トプレのジ良／Ｉ（Ｉｔ
’／．）第４図
第６図
（Ａ）
フルルビプロフ工ン
物１１灼５几合物
〔１イ４ζクテａイオζ
Ｃ−５ ％ト”Ｊ＞４ｆＬ （ｉｔ’／０）Ｃ−Ｓ
矢トプンＱｉＬＣ１ｔ’ム》（κ）
（Ｌ）
ＣＢ）
インドノタン／
勺μ！．的三見＋物
固イネ分１じ（イ４（
Ｃ−５
七トザンの濃度（吏ｔ’／．）
Ｃ−Ｓ へトプンりｉＬＣｉ量．’／．）２ｅ（”）
第５図
（Ａ）
ＣＢ）
トリアムシノ０ン
５客二吋間（分）
薄払吟関（捌）
薄代崎閏（分》
三写よ叶間（分）
第５図
（Ｅ）
ＣＧ）
フェードイン
５９ ’；： ａ？間（・栃
第６図
（Ｃ）
シゴＮシノ
物１５−的ジ毘番・物
（Ｄ）
トリアムンノロン
物理的形晃合物
［ロイ爪クク唱ｉ（イ４（
２θ（＠）
溶二吟間（分）
方じ早 Ｃ０１．）／ｌイ固Ｏりｔ剤
（Ａ）
Ａｓ．
（”Ｃ）
（Ｂ）
インドメタンン
５１度（゜Ｃ）FIG. 1 is a graph showing the results of Example 1, FIGS. 2 and 3 are graphs showing the results of Example 2, and FIGS.
L) is a graph showing the results of Example 3, and Figures 5(A) to (
G) is a graph showing the results of Example 4, and FIGS. 6(A) to (
D) is a graph showing the results of Example 5, FIG. 7(A), (
B) is a graph showing the results of Example 6, and FIG. 8 is a graph showing the results of Example 8.
This is a graph showing the results. Agent Patent Attorney Sei Yanagihara Diagram 2 C-5 Hetopun's filtration (t amount!) Figure 3 Soukinma (minutes) C-5 version Topuntsu thick/t (it'/.) No. 4Figure 4 (A) CB) (E) (F) C-5-N}Pun no Ko/I (tt @/o) C-S
Thickness of Hetop〉? (Weight, amount.'/.) (G) (H) (-5xt4's 5 degree of agriculture (it'/.) C-5 Kotopun Rino/iCt amount'/.) C-S Hetopun no Me /
I (!Amount 0l.) C-S Yotopre no Jira/I (It
'／． ) Fig. 4 Fig. 6 (A) Flurbiprof construction material 11 burnt 5 compound [1 I 4 ζ kte aio ζ C-5
YatopunQiLC1t'mu》(κ) (L) CB) Indonotan/ 勺μ! ．． Figure 5 (A ) CB) Triamshino 0 on 5 customers 2 吾 ま (minutes) Usubai Ginseki (捌) Usudaizaki Ran (minutes) Sanshayo Kanoma (minutes) Figure 5 (E) CG) Fade in 59';: Between a? Ginma (minutes) Hojihaya C01.)/l hard temperature agent (A) As. (''C) (B) Indomethane 51 degrees (°C)
Claims (1)
組成物。(1) A pharmaceutical composition containing low molecular weight chitosan and a poorly soluble drug.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63285566A JP2638156B2 (en) | 1988-11-11 | 1988-11-11 | Pharmaceutical composition |
| EP89912499A EP0443027B1 (en) | 1988-11-11 | 1989-11-10 | Drug composition |
| PCT/JP1989/001152 WO1990004980A1 (en) | 1988-11-11 | 1989-11-10 | Drug composition |
| DE89912499T DE68907609T2 (en) | 1988-11-11 | 1989-11-10 | MEDICINAL COMPOSITION. |
| US08/203,863 US5474989A (en) | 1988-11-11 | 1994-03-01 | Drug composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63285566A JP2638156B2 (en) | 1988-11-11 | 1988-11-11 | Pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02131434A true JPH02131434A (en) | 1990-05-21 |
| JP2638156B2 JP2638156B2 (en) | 1997-08-06 |
Family
ID=17693212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63285566A Expired - Lifetime JP2638156B2 (en) | 1988-11-11 | 1988-11-11 | Pharmaceutical composition |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0443027B1 (en) |
| JP (1) | JP2638156B2 (en) |
| DE (1) | DE68907609T2 (en) |
| WO (1) | WO1990004980A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04180901A (en) * | 1990-11-15 | 1992-06-29 | Kitosan Honpo:Kk | Dissolution of chitosan and substance containing dissolved chitosan |
| US5812828A (en) * | 1995-06-01 | 1998-09-22 | Centerline Software, Inc. | Function simulation |
| WO1999022739A1 (en) * | 1997-10-31 | 1999-05-14 | Taisho Pharmaceutical Co., Ltd. | Medicinal steroid compound composition |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2217360A1 (en) * | 1995-04-04 | 1996-10-10 | Otsuka Pharmaceutical Co., Ltd. | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation |
| AU2712197A (en) * | 1996-05-09 | 1997-11-26 | Taisho Pharmaceutical Co., Ltd. | Micellar aqueous composition and method for solubilizing hydrophobic drug |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS597117A (en) * | 1982-07-02 | 1984-01-14 | Teijin Ltd | Pharmaceutical containing chitosan |
| DE3527482A1 (en) * | 1984-07-31 | 1986-02-06 | Fuji Spinning Co., Ltd., Tokio/Tokyo | METHOD FOR PRODUCING GRAINY POROUS CHITOSAN |
-
1988
- 1988-11-11 JP JP63285566A patent/JP2638156B2/en not_active Expired - Lifetime
-
1989
- 1989-11-10 WO PCT/JP1989/001152 patent/WO1990004980A1/en active IP Right Grant
- 1989-11-10 EP EP89912499A patent/EP0443027B1/en not_active Expired - Lifetime
- 1989-11-10 DE DE89912499T patent/DE68907609T2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04180901A (en) * | 1990-11-15 | 1992-06-29 | Kitosan Honpo:Kk | Dissolution of chitosan and substance containing dissolved chitosan |
| JPH0681763B2 (en) * | 1990-11-15 | 1994-10-19 | 株式会社キトサン本舗 | Chitosan dissolution method and chitosan dissolution substance |
| US5812828A (en) * | 1995-06-01 | 1998-09-22 | Centerline Software, Inc. | Function simulation |
| WO1999022739A1 (en) * | 1997-10-31 | 1999-05-14 | Taisho Pharmaceutical Co., Ltd. | Medicinal steroid compound composition |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0443027A1 (en) | 1991-08-28 |
| WO1990004980A1 (en) | 1990-05-17 |
| DE68907609T2 (en) | 1994-03-10 |
| EP0443027B1 (en) | 1993-07-14 |
| JP2638156B2 (en) | 1997-08-06 |
| EP0443027A4 (en) | 1991-10-16 |
| DE68907609D1 (en) | 1993-08-19 |
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